9 alpha,11-dimethyl-substituted steroids

ABSTRACT

THE COMPOUNDS ARE 9A, 11-DIMETHYL-SUBSTITUTED STEROIDS OF THE ESTRANE-TYPE, E.G. 9A, 11-DIMETHYL-17A-ETHYNYLESTRA4-EN-17B-OL-3-ONE. THE COMPOUNDS ARE USEFUL AS PHARMACEUTICALS.

"United States Patent Oifice 3,778,434 Patented Dec. 11, 1973 3,778,4349 ALPHA, ll-DIMETHYL-SUBSTITUTED STEROIDS Robert V. Coombs, Chatham,NJ., assignor to Sandoz-Wander, Inc., Hanover, NJ. No Drawing. FiledApr. 20, 1972, Ser. No. 245,968 Int. Cl. C07c 173/00 US. Cl. 260--239.55C 27 Claims ABSTRACT OF THE DISCLOSURE The compounds are9u,11-dimethyl-substituted steroids of the estrane-type, e.g.9a,1l-dirncthyl-17a-ethynylestra- 4-en-17 3-ol-3-one. The compounds areuseful as pharmaceuticals.

This invention relates to steroidal compounds, and more particularly to9a,11-dimethyl-substituted-estranes, to the preparation of suchcompounds and to intermediates in the preparation of such compounds, aswell as to compositions containing such compounds and to the use of suchcompositions.

The compounds of the invention may be conveniently represented by thestructural Formula I:

wherein R is x0, or

wherein R is a hydrogen atom, methyl, or ethynyl; and

R is a hydrogen atom, or alkanoyl having from 2 to 4 carbon atoms, e.g.acetyl, propionyl and butyryl, including isomeric forms where theyexist, and is preferably unbranched; and ring A has the structure q/ bkor (c) R is a hydrogen atom, alkyl having from 1 to 4 carbon atoms, e.g.ethyl, methyl, propyl or butyl, including isomeric forms where theyexist and is preferably unbranched, or alkanoyl having from 2 to 4carbon atoms, e.g. as described above; provided that when ring A is oftype (a) or (b) then R is not 0x0 or wherein IIIH I Accordingly,Compounds I include 3 classes of compounds depending upon the structureof ring A present, i.e. Compounds Ia, Ib or wherein R R and 'R are asdefined above, and R is methyl or ethynyl.

Compounds of Formula 10, are obtainable by a multistep process. Theprocess for the preparation of a Compound Ic wherein R is oxo and R isthe same as R, as defined above, but is other than a hydrogen atom oralkanoyl, i.e. a Compound Icl, is conveniently represented by ReactionScheme A below; wherein, Kt is a ketal group which is suitable formasking an oxo group, such as wherein each R is methyl, or they may bejoined to form a short alkylene chain, e.g. having 2 or 3 carbon atoms,i.e. ethylene or n-propylene:

Reaction Scheme Step b Hydrolysis Step Hydrogenation O gi In thepreparation of a Compound Icl, the starting materials, i.e. Compounds A,are known and their preparation is described in the literature, e.g.Belgian Patent 753,779, or where not known, they may be prepared in amanner analogous to that for preparing the known compounds.

Step a, the introduction of a hydroxy and a methyl group at thell-position, is achieved by reacting a Compound A with a metallo-organicreagent bearing a methyl group, e.g. a Grignard reagent, underconditions conventionally employed in carrying out a Grignard reaction.The selection of the particular reagent and reaction conditions are notcritical and are within the skill of persons skilled in the art. Forexample, a methyl-active metal reagent may -be used, wherein the activemetal is an alkali metal such as lithium, sodium or potassium or apolyvalent metal, such as aluminum, or magnesium bromide or iodide.Sfirch reagents are well-known and many are commercially available.

Step a involves two stages, i.e. a condensation stage which results inthe formation of an intermediate which is the ll-methyl-ll-O-metallicsalt of the resulting Compound B, the metallic cation being contributedby the metallo-organic reagent. The intermediate is then hydrolyzed toyield the free ll-hydroxy compound, i.e. the Compound B. The reactionmay be conveniently carried out, e.g. at a temperature of from about 80to +60 C. and preferably from about -50 to +30 C. in an anhydrousaprotic solvent or medium suitable for reactions involving ametallo-organic reagent, e.g. an ether, such as tetrahydrofuran. Thehydrolysis of the reaction product may be carried out in the mannerconventionally used in hydrolyzing Grignard adducts, for example, in anaqueous medium, e.g. by water or a highly concentrated aqueous solutionof ammonium chloride or dilute aqueous acid or alkal e so utio (Icl) InStep b the ketal group of Compound B is cleaved by hydrolysis underaqueous acid conditions. Step b should be carried out under relativelymild acid conditions, e.g. in acid media with pH value above about 3 andpreferably between 3 and 5 for a prolonged period, e.g. for a period offrom about A to 3 hours. Organic acid, such as oxalic acid or aceticacid may be used to provide the acidic conditions. Step b may be carriedout at temperatures of, e.g. from about 0 to C., preferably from about15 to 50 C. An inert water-miscible solvent may be employed, such as alower alkanol, e.g. methanol. Where the acid reactant is liquid it maybe employed in excess to serve as solvent e.g. acetic acid. Co-solventsmay also be used.

Step 0 involves acetylating the ll-hydroxy function of a Compound Cunder conditions which are not strongly acidic. For example, theacetylation may be carried out using calcium hydride, held in aceticanhydride at temperatures of from about 80 to C., preferably at reflux;no solvent being required as the acetic anhydride can serve as solvent.

In Step d, Compound D is submitted to pyrolyzing conditions whereby thell-methyl, ll-acetoxy system thereof is converted to an ll-methylenefunction, yielding a Compound E. The pyrolysis may be achieved byheating a Compound D at e.g. about 225 to 260 C. at reduced pressure.

In Step e, the conversion of the ll-methylene function of a Compound Eto a methyl group to obtain the corresponding Compound Icl, is achievedby hydrogenation. The hydrogenation may be carried out in theconventional manner, e.g. employing an inert solvent or medium, such asa lower alkanol, e.g. methanol, with agitation at moderate temperatures,e.g. at from about 15 to 60 C., preferably at about 20 to 30 C., in ahydrogen atmosphere in the presence of a noble metal catalyst which maybe finely divided on a carrier; 5% palladium on charcoal (carbon) beingpreferred.

As will be appreciated, Compounds Icl may be converted to otherCompounds Ic by conventional means. The 3-alkoxy function of a CompoundIcl may be cleaved by conventional means for cleaving an ether linkageto obtain a Compound Ic wherein R is a hydrogen atom. For example, thecleavage may be carried out by heating the 3- alkoxy-compound withpyridine-HCl at from about 100 to 200 C., preferably at about 180 C. Theresulting 3- hydroxy-compound may then be alkanoylated by conventionalmeans to obtain a Compound Ic wherein R is an alkanoyl group.

Compounds Icl may also serve as intermediates for Compounds In or Ib, asmay be conveniently represented by Reaction Scheme B, which follows;wherein R and R are as defined above, and R is the same as R but isother than a hydrogen atom, i.e. it is an alkanoyl group; and CompoundsIal and Ibl are the same as Compounds Ia and 112, wherein R is ahydrogen atoms:

REACTION SCHEME B CH; H8O

Step h Organo metallic reagent on on Gig:- HaC ,1 GEL/{ 19 Ru IHBtepIL-Zi ydro vs S 6H:

(Ibl) Step l-1 st F3 Hydrolysisl D rearrangement I R rangement Step 1Aeylatlon OR on, E 0] In Step f a Compound Icl is converted to itscorresponding Compound G by reducing the aromatic unsaturation, i.e. the1,3,5(10)-double bond system of ring A, to a 2,5 10)-dien system, andalso reducing the 17-oxo function. This may be accomplished by employingthe socalled Birch reduction, which broadly involves use of a lightmetal, e.g. lithium, and tert.-butanol, in liquid ammonia at reducedtemperatures (suflicient to maintain the ammonia in a liquid state); asthe ammonia can serve as the reaction medium, no solvent is required,but can be used, e.g. benzene or tetrahydrofuran.

In Step g, the 17-hydroxy function of a Compound G is oxidized to an oxofunction, yielding the corresponding Compound H. The oxidation may beaccomplished by those means conventionally used for oxidizing asecondary aliphatic hydroxy to a carbonyl, which do not involve stronglyacidic conditions, for example, by employing the so-called Oppenaueroxidation, which broadly involves oxidizing a hydroxy function in thepresence of a metallic alkoxide and a ketone, e.g. aluminum isopropoxideand 2- butanone, e.g. at temperatures of about 60 to 130 C., in an inertorganic solvent, such as benzene, toluene and the like.

In Step h, a 17-oxo compound (a Compound H) is converted to itscorresponding l7/3-hydroxy-l7u-methyl or ethynyl-substituted analog,i.e. a Compound II.

In preparing a Compound II (Step h) a metallo-organic reagent bearingthe desired group is employed. A 170:- methyl, l7 3-hydroxy compound canbe obtained by adapting the procedure described for Step a, above. A17ozethynyl, 17B-hydroxy substituted Compound II, may be prepared in amanner analogous to that of Step at. A particularly convenient method ofpreparing a Compound II wherein R is ethynyl is to use as themetallo-organic reagent lithium acetylide/ethylenediamine complex indimethyl sulfoxide or dimethyl-acetamide, under the conditions of Stepa.

A Compound II may be converted to its corresponding Compound Ia (Stepi-l) by hydrolysis-rearrangement wherein the3-alkoxy-2,5(l0)-dien-system is converted to a 3-oxo-4en-system. Suchconversion may be accomplished by employing the aqueous acidicconditions of Step b for a prolonged period, e.g. over 3 hours.Alternatively, Step i-l may be carried out under vigorous aqueous acidicconditions, i.e. at about pH value of 3 or lower, e.g. between 1 and 2;the acidic conditions being provided by, e.g. oxalic acid, p-toluenesulfonic acid or a mineral acid, such as hydrochloric acid. Theconversion is accomplished under such vigorous conditions in arelatively short time, e.g. less than 3 hours. Treatment of a CompoundII with the mild acidic conditions of Step b for a relatively shortperiod of time (Step i-2) yields the corresponding Compound Ib. ACompound Ib can be converted to its corresponding Compound Ia byrearrangement (Step i-3). Step i-3 may suitably be carried out bysubjecting a Compound Ib to acid or basic conditions. The process may becarried out under either aqueous or non-aqueous conditions.

Basic rearrangement may suitably be eflected in an inert organicsolvent, such as dioxane, methanol or ethanol. A suitable reactiontemperature is from 20 to C., conveniently from 20 to 30 C., or at thereflux temperature of the reaction mixture. Suitable reaction timesvary, for example from A hr. to 6 hrs. Aqueous basic conditions mayconveniently be obtained by using, for example, aqueous sodium orpotassium hydroxide, preferably at a concentration of from 0.01 N to 2N. Where non-aqueous conditions are employed, the basic conditions areconveniently provided by using an alkali metal lower alkoxide, e.g.sodium methoxide.

Acid rearrangement may suitably be carried out under the conditionsdescribed above in connection with Step i-l. However, the aqueous natureof the conditions, essential in Step i-l, are not essential in therearrangement and, accordingly, the solvent need not be water-miscible.

In Reaction Scheme B, Step h is shown to be applied to a Compound H.However, where a Compound 10 wherein R is l7B-hydroxy, 17a-methyl orethynyl is desired, a Compound Icl may be treated in a manner analogousto Step h to obtain such a compound. A Compound Ic wherein each of R andR is a hydrogen atom may be obtained by reducing the 17-oxo function ofa Compound Icl. The reduction may be accomplished by treatment in theconventional manner with a light metal or complex hydride, e.g. NaB-H orLiAlH, under conditions conventionally applied in carrying out such areduction in an aprotic organic medium essentially free of water, e.g.ethanol or ethanol-methylene chloride for NaBH, and tetrahydrofuran forLiAlH In Reaction Scheme B, acylation of Compounds Ial and Ibl is shownto yield the corresponding compounds wherein R is alkanoyl, as definedabove. However, Compounds 10 wherein R is a hydrogen atom, as well asCompounds Ia, lb or 10 wherein R is a hydrogen atom, i.e. Compounds Ibearing a hydroxy group at any of positions 3- and 17-, may be acylatedto obtain those Compounds I wherein any of R and R is alkanoyl asdefined above (Step 7').

The Step i may be effected by processes known per se for the acylationof steroid alcohols. With respect to compounds of Class 10 having twohydroxy groups, it will be noted that, a hydroxy group at the 3-positionis phenolic and a hydroxy group at the H S-position is secondary ortertiary. As one skilled in the art will be aware, the ease of acylationis phenolic secondary tertiary, and the ease of re-saponification isclearly phenolic secondary tertiary. Accordingly, acylating agents andthe stringency of acylating conditions can be chosen depending on thedegree of acylation required employing conventional techniques. Suitableacylating agents for the 3- position include acids, acyl halides andacid anhydrides of formulae acyl-OH, acyl-Hal and (acyl) O,respectively, therein acyl is alkanoyl as defined above, Hal signifiesbromine or chlorine, and mixtures thereof. Where the desired acyl moietyis acetyl, a preferred acylating agent is acetic anhydride. In carryingout the acylation, inert solvent may be employed or excess acylatingagent may serve as solvent. An acid-binding agent, e.g. pyridine, ispreferably used. Preferred temperatures vary between l and 50 C. Foracylation of both positions, more stringent conditions may be used,characterized by the presence of a strongly acidic catalyst, e.g.p-toluenesulphonic acid, perchloric acid and the like. If such catalystsare used, in addition to the above-listed acylating agents, enolacylates, preferably esters of isopropenyl alcohol, e.g. isopropenylacetate, may also be employed. The considerations involved are wellwithin the scope of one skilled in the art. The method of Step c canalso be adapted to a 17/3-hydroxy group.

Furthermore, the diester form of Compounds Ic may be selectivelysaponified employing conventional means, e.g. by treatment withmethanolic potassium bicarbonate, to obtain the corresponding3-hydroxy-l7,3-acyloxy-substituted Compound Ic. Hence, one skilled inthe art can use such knowledge to obtain the desired combination of freehydroxy and acylated positions.

An alternative method of preparing a Compound Ia or Ib wherein R ismethyl, is to submit a Compound Icl to the conditions of Step Itemploying a methyl-contributing organo-metallic reagent to obtain aCompound wherein R is methyl and R is a hydrogen atom, to then submitthat compound to the conditions of Step 1 to obtain a l7a-methyl analogof Compound G, i.e. a Compound II, which can then be submitted toStep(s) i to obtain the corresponding Compound Ia or Ib.

Compounds I of this invention are useful because they possespharmacological properties in animals and many can be used asintermediates for other Compounds I which possess such properties. Inparticular, those Compounds Ia wherein R is ethynyl and R is as definedabove, have progestational activity and are useful as fertility controlagents in birds and mammals and in regulating estrus or the menstrualfunction in mammals. The progrestational activity of said compounds isindicated by the well-known Clauberg test involving observation ofuterine changes in immature female white rabbits given 0.02 to 1milligram of active agent.

Compounds I wherein R is methyl and R is as defined above, and CompoundsIb wherein R is methyl and R is as defined above, haveanabolic-androgenic activity and are useful in increasing theaccumulation of body protein and in reversing negative nitrogen balancein birds and mammals. The anabolic-androgenic activity of said compoundsis indicated by well-known test methods, such as by observing theincrease in the weight of the ventral prostate glands and of the levatorani muscles of castrated immatuure male white rats, e.g. as described byEisenberg et al. in J. Pharmacol. Exper. Therap. 99; 38-44 (1950) given0.02 to 1 milligram of active agent.

Compounds 10 have estrogenic activity and are useful in replacementtherapy for estrogen deficiencies, fertility control in birds andmammals and regulation of estrus or the menstrual cycle in mammals. Theestrogenic activity as indicated by observing increase in white mouseuterine weight, e.g. as described in Endocrinology 65, 265 (1959) or byobserving for cornification of vaginal epithelium of adult femaleovariecomized white rats scored according to the method of Biggers andClaringbold, when said animals are given from 0.1 to 10 milligrams ofactive agent.

The Compounds Ib wherein R is ethynyl and R is as defined above possessa combination of estrogenic and progestational activity and aretherefore useful in controlling fertility of birds and mammals andregulating estrus or the menstrual cycle of mammals. Said estrogenic andprogestational activities being indicated by the pertinent methodsdescribed above.

These compounds may be combined with a solid or liquid pharmaceuticallyacceptable carrier or adjuvant in the conventional manner. They may beadministered orally or parenterally. The dosage will vary depending uponthe mode of administration utilized and the particular compoundemployed. However, in general, satisfactory results are obtained whenCompounds Ia or Ib are administered at a daily dosage of from about 0.01to 10 milligrams for the above-described pertinent uses and Compounds Icare administered at a daily dosage of from about 0.1 milligram to 30milligrams for the above-described pertinent uses. As is appreciated bythose skilled in the art, the dosages are independent of body weight.The compounds are preferably administered in soild orally administrableform, e.g. as tablets or capsules.

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques which contains thefollowing:

Ingredient: Parts by weight 904,11dimethyl-17a-ethynylestra-4-en-1713-01-3- one 0.5 Tragacanth 2 Lactose89 Cornstarch 5 Talcum 3 Magnesium stearate 0.5

The following examples are presented as illustrative of the invention.In the examples, all temperatures are centrigrade, and room temperatureis 20 to 30 C., unless indicated otherwise.

Compound E are also useful for the same uses and may be administered inthe same dosage and manner as described above for Compounds Ic.

EXAMPLE 1 904,1 1-dimethyl-3-methoxyestra-1,3,5( 10 -trien- 17-one O CH:C

Step A.17,17-ethylenedioxy-9u,1 1-dimethy1-3-methoxyestra-1,3,5(10)-trien-1 1-ol and the solvent is removed in vacuo. The residue iscrystallized from methanol to give 17,17-ethylenedioxy-9a-11- dimethyl 3methoxy-estra-1,3,5(10)-trien-1l-ol, M.P. 104-106".

Step B.9a, 1 1-dimethyl-3-methoxyestra- 1,3,5(10)-trien-11-ol-17-one Asolution of 4.2 g. of the product of Step A above, in 40 ml. of glacialacetic acid and 10 ml. of water is heated at 60 for 30 min. It is thencooled and poured onto ice and 10% sodium bicarbonate soluton. Theorganic material is extracted with ether and after drying over Na S theether is removed under reduced pressure. The crystalline residueobtained is recrystallized from ether to give 9u,1 1 dimethyl,3-methoxyestra-l,3,5(10)-trien-ll-ol-17- one, M.P. 170172.

Step C.--1 l-acetoxy-9u,1 1-dimethyl-3-methoxyestra- 1,3,5)-trien-17-one A suspension of 600 mg. of calcium hydride (powdered) in6-0 ml. of acetic anhydride is stirred and refluxed for /2 hr. To thisis added 3 g. of the above ll-hydroxy product of Step B in one portionas a solid and the stirring and refluxing is continued for 65 hrs. Themixture is then cooled and poured onto ice and 10% sodium bicarbonateaqueous solution. When the foaming has subsided, the aqueous mixture isextracted with ether and the ether extract is washed first with fresh10% bicarbonate solution and then water. After drying over Na SO theether is removed and the residue is crystallized from ether to give 11acetoxy 901,11 dimethyl-3-methoxyestra-1,3,5(l0)- trien-17-one, M.P.174-176".

Step D.3-methoxy-l l-methylene-9a-methylestra- 1,3,5 10) -trien-17-oneThe solid ll-acetoxy steroid of Step C, 2.5 g. is heated in a smallflask under a vacuum of mm. of mercury at a temperature of 230 to 245,for about 4 hrs. The flask is then cooled and the residue is dissolvedin chloroform. This chloroform solution is filtered through a shortcolumn of silica gel and then evaporated to dryness. The residue iscrystallized from ether to give 3-methoxy-11-methylene9a-methylestra-1,3,5(10)-trien-17-one, M.P. 190-191 Step E.-9a,11-dimethyl-3-methoxyestra- 1,3,5(10)-trien-17-one A solution of 300 mg.of the product of Step D above, in ml. of methanol containing 50 mg. ofa 5% palladium on carbon catalyst in suspension is shaken under anatmosphere of hydrogen until uptake ceases (about 5 hrs.) The suspensionis then filtered and the filtrate evaporated to dryness. The residue iscrystallized from methanol to give 9u,1 1-dimethyl-3-methoxyestra-1,3,510)-trien-17- one, M.P. 128-130.

Hard-filled capsules containing 1 mg. of 9a,11-dimethyl- 3 methoxy1,3,5(10) trien 17 one and 299 mg. of lactose may be prepared byconventional techniques. Such capsules are useful in estrogenreplacement therapy or in controlling fertility, in female warm-bloodedanimals at a dose of one capsule per day.

EXAMPLE 2 9a, 1 1-dimethyl-17a-ethynylestra-4-en-17,8-01-3-one StepA.-9a,11-dimethyl-3-methoxyestra- 2,5(10)-dien-17;3-ol

A solution of 700 mg. of9a,11-dimethyl-3-methoxyestra-1,3,5(10)-trien-17-one steroid in 50 ml.of tetrahydrofuran and 70 ml. of tert.-butanol is added to 100 ml. ofliquid ammonia under reflux. To this solution is added 2 g. of lithiumWire, portion-wise, and the resulting blue solution is stirred underreflux using a Dry Ice condenser for 5 hrs. The ammonia is then allowedto evaporate and 20 ml. of methanol is added dropwise to the residue,followed by 20 ml. of benzene and 20 ml. of saturated aqueous sodiumchloride solution. The organic base is separated, washed with water,dried (over Na SO and evapo- 10 rated to obtain a residue which iscrystallized from ether/ heaxne, l/ 1, to give904,11-dimethyl-3-methoxyestra-2,5- (10)-dien-l7/3-ol, M.P. 147-150".

Step B.9a,11-dimethyl-3-methoxyestra- 2,5 10) -dien-17-one A mixture of800 mg. of 9u,11-dimethyl-3-methoxyestra-2,5-dien-17p-ol, 1 g. ofaluminum isopropoxide, 10 ml. of Z-butanone and 10 ml. of benzene isstirred and refluxed for 17 hrs. It is then cooled and poured onto iceand 20 ml. of saturated aqueous sodium bicarbonate solution. The aqueousmixture is extracted with 10 n11. benzene and the organic phase iswashed with saturated aqueous sodium chloride solution and dried (Na SOAfter removal of the solvent, the residue is crystallized from ether togive 9m,11- dimethyl-3-methoxyestra-2,5(10)- dien-17-one, M.P. 158160.

Step C.9oc, 1 l-dimethyl-l7a-ethynyl-3-methoxyestra-2,5 l0)dien-17p-o1To a solution of 350 mg. of9a,1l-dimethyl-3-methoxyestra-2,5(10)-dien-17-one in 15 m1. of dimethylsulfoxide is added 1 g. of lithium acetylide/ethylenediamine complex.The mixture is stirred at room temperature for 4 hrs. under nitrogen andit is then poured onto ice and extracted with 15 ml. methyl chloride.The organic phase is washed with water and dried (Na SO Removal of thesolvent gives a non-crystalline residue, shown by infra-red analysis(I.R.) to contain no carbonyl grouping, which is used as such for thesubsequent step.

Step D.-9a,l1-dimethyl-17aethynylestra- 4-en-17fi-ol-3-one A solution of460 mg. of the crude product obtained in Step C above, in 20 ml. ofmethanol and 2 ml. of 2 N hydrochloric acid is maintained at atemperature of 50 for 1 /2 hrs. and then concentrated in vacuo. Theresidue is dissolved in methylene chloride and washed with 10% aqueoussodium bicarbonate solution. After drying over Na SO the solvent isremoved and the residue is applied to thick layer chromatography platesby dissolving it in a minimum amount of chloroform. The plates aredeveloped using chloroform/1% methanol, 3 times, and the main band whichis strongly absorbing in the ultra-violet region (U.V.) is removed. Thesteroid is extracted with ethyl acetate and removal of the ethyl acetategives a residue which is crystallized from ether/hexane, 1/1. Thus isobtained the title compound, M.P. 168-170.

Repeating the procedure of Step C of this example, but using in place ofthe 9a,l1-dimethyl-3-methoxyestra-2, 5(10)-dien-17-one used therein anequivalent amount of 911,11 dimethyl3-methoxyestra-1,3,5(10)-trien-17-one, there is analogously obtained17B-ethynyl-9a,1l-dimethyl- 3-methoxyestra-1,3,5 10) -trien-l7j3-ol.

EXAMPLE 3 911,11,17a-trimethylestra-4-end7fl-ol-3-one HsC Step A.-3-methoxy-9a, 1 1,17a-trimethylestra- 2,5(10)-dien-17/3-ol 1 1 solutionand extracted with ether. The ether solution is washed with water anddried (Na SO Removal of the ether gives a non-crystalline residue,showing no carbonyl absorption in the LR, which is used as such for thenext step.

Step B.-9oc,l 1,17a-trimethylestra-4-en-17Bol-3-one The non-crystallinesteroid obtained in Step A, above, 230 mg. is treated with 10 ml. ofmethanol and 2 m1. of 2 N hydrochloric acid as described under Step D ofExample 2. Similar thick layer chromatography and removal of the U.V.absorbing band gives a residue which is crystallized from ether. Thus isobtained the title compound, M.P. 142-145 Repeating the procedure ofStep A of this example, but using in place of the90,1l-dimethyl-S-methoxyestra- 2,5(10)-dien-l7-one used therein, anequivalent amount of 9a,11-dimethyl 3 methoxyestra-1,3,5(10)-trien-17-one, there is analogously obtained3-methoxy-9a,11-17atrimethylestra-1,3,5 10) -trien- 1713-01.

Additional exemplary compounds of the invention are:

(a) 9a,1 l-dimethylestra-1,3,5 l)-trien-3-ol-17-one,

(b) 3-acetoxy 901,11 dimethylestra-1,3,5()-trien- 17-one,

(c) 3-acetoxy 911,11 dimethyl 17 ethynylestra- 1,3,5 10) -trien-17/3-ol,

(d) 911,11 dimethyl 3 n propoxyestra 1,3,5(10)- trien-l7-one,

(e) 1713' acetoxy 911,11 dimethyl 17a ethynylestra-4-en-3-one, and

(f) 911,1l-dimethyl-17a-ethynylestra-5( 10)-en-1718-ol-3- one.

What is claimed is:

1. A compound of the formula R1 cm I wherein R is oxo, or

Hug

wherein R is a hydrogen atom, methyl, or ethynyl; and R is a hydrogenatom, or alkanoyl having from 2 to 4 carbon atoms; and

ring A has the structure wherein R is a hydrogen atom, alkyl having from1 to 4 carbon atoms, or alkanoyl having from 2 to 4 carbon atoms.

provided that when ring A is of type (a) or (b), then R is not oxo or 2.A compound of claim 1, wherein ring A is of type (a), and R is asdefined in claim 1.

3. The compound of claim 2 which is 9oz,11-dimethyl-17a-ethynylestra-4-en-l7 3-ol-3-one.

4. The compound of claim 2 which is 9a,ll,17a-trimethylestra-4-en-17B-ol-3-one.

5. A compound of claim 1 wherein ring A is of type (b) and R is asdefined in claim 1.

6. A compound of claim 1 wherein ring A is of type (c) and R and R areas defined in claim 1.

7. A compound of claim 6 wherein R is oxo.

8. The compound of claim 7 which is 9a,11-dimethyl-3-methoxyestra1,3,5(10)-trien-17-one.

9. A compound of claim 6 wherein R is 17a-ethynyl, 17fl-hydroxy.

10. A compound of the formula CECH 16. The compound of claim 15 which is9a,11-dimethyl-17a-ethynyl-3-methoxyestra-2,5 10 -dien-17fl-ol.

17. A compound of the formula wherein R is as defined in claim 10, and Ris oxo or Kt where Kt is wherein n is 2 or 3.

18. A compound of claim 17, wherein R is 0x0.

19. The compound of claim 18 which is 9a,11-dimethyl-3-methoxyestra-l,3,5 l0-trien-1 l-01-17-one.

20. A compound of claim 17, wherein R is Kt.

21. The compound of claim 20 which is 9a,11-dimethyl- 1717-ethylenedioxy-3-methoxyestra-1,3,5 10)-trien-1 l-ol.

22. A compound of the formula wherein R is as defined in claim 10, and Ris 23. A compound of claim 22 wherein R 0 O GHa,

0 0 HIGH:

24. The compound of claim 23 which is ll-acetoxy- 26. The compound ofclaim 25 which is 3-methoxy-1l- 20 methylene-9a-methylestra-1,3,5 10)-trien- 17-0ne.

14 27. A compound of claim 1 wherein ring A is of type (a) and R is 0RL-CECH 5 wherein R is as defined in claim 1.

References Cited UNITED STATES PATENTS 10 3,299,108 1/1967 Bal'an260397.5 3,377,366 4/1968 Baran 260397.45 3,418,327 12/1968 Buzby et al.260397.4 3,465,010 9/ 1969 Baran 260397.5 3,541,067 11/1970 Bergstrom260397.45 15 3,652,606 3/1972 Baran et a1. 260.397.5 3,655,652 4/1972Coombs et a1. 260239.55

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

